Frovatriptan (T3D2954)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (2)XML
Targets (2)
Record Information
Version2.0
Creation Date2009-07-21 20:28:08 UTC
Update Date2014-12-24 20:25:54 UTC
Accession NumberT3D2954
Identification
Common NameFrovatriptan
ClassSmall Molecule
DescriptionFrovatriptan (Frova™) is a triptan drug developed by Vernalis for the treatment of migraine headaches, in particular those associated with menstruation. The product is licensed to Endo Pharmaceuticals in North America and Menarini in Europe.[1] Frovatriptan causes vasoconstriction of arteries and veins that supply blood to the head. It is available as 2.5 mg tablets. Frovatriptan has mean terminal elimination half-life of approximately 26 hours, which is substantially longer than other triptans. Frovatriptan is available only by prescription in the United States, where a secondary New Drug Approval (sNDA) was filed in July 2006[2] and which is currently pending.[3] The FDA anticipates completing its review of this application on or before the current PDUFA (Prescription Drug User Fee Act) review date of August 19, 2007. If the sNDA is approved, Frova™ will be the only medication indicated in the U.S. for the short-term prevention of menstrual migraine (MM).
Compound Type
  • Amide
  • Amine
  • Anti-Inflammatory Agent
  • Anti-Migraine Agent
  • Drug
  • Ester
  • Metabolite
  • Organic Compound
  • Serotonin Agonist
  • Serotonin Receptor Agonist
  • Synthetic Compound
  • Vasoconstrictor Agent
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
Allergo filmtabletten
Frova
Frovatriptan succinate
Frovelan
Miguard
Chemical FormulaC14H17N3O
Average Molecular Mass243.304 g/mol
Monoisotopic Mass243.137 g/mol
CAS Registry Number158747-02-5
IUPAC Name(3R)-3-(methylamino)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide
Traditional Namefrovatriptan
SMILES[H][C@]1(CCC2=C(C1)C1=C(N2)C=CC(=C1)C(O)=N)NC
InChI IdentifierInChI=1S/C14H17N3O/c1-16-9-3-5-13-11(7-9)10-6-8(14(15)18)2-4-12(10)17-13/h2,4,6,9,16-17H,3,5,7H2,1H3,(H2,15,18)/t9-/m1/s1
InChI KeyInChIKey=XPSQPHWEGNHMSK-SECBINFHSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as carbazoles. Carbazoles are compounds containing a three ring system containing a pyrrole ring fused on either side to a benzene ring.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassIndoles and derivatives
Sub ClassCarbazoles
Direct ParentCarbazoles
Alternative Parents
Substituents
  • Carbazole
  • Indolecarboxamide derivative
  • Indolecarboxylic acid derivative
  • 3-alkylindole
  • Indole
  • Aralkylamine
  • Benzenoid
  • Heteroaromatic compound
  • Pyrrole
  • Amino acid or derivatives
  • Carboxamide group
  • Primary carboxylic acid amide
  • Carboxylic acid derivative
  • Secondary aliphatic amine
  • Azacycle
  • Secondary amine
  • Hydrocarbon derivative
  • Organic oxide
  • Organic nitrogen compound
  • Amine
  • Organopnictogen compound
  • Organonitrogen compound
  • Organooxygen compound
  • Organic oxygen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
SolubilitySoluble
LogP0.9
Predicted Properties
PropertyValueSource
Water Solubility0.12 g/LALOGPS
logP1.2ALOGPS
logP1.08ChemAxon
logS-3.3ALOGPS
pKa (Strongest Acidic)14.54ChemAxon
pKa (Strongest Basic)10.42ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area70.91 ŲChemAxon
Rotatable Bond Count2ChemAxon
Refractivity71.84 m³·mol⁻¹ChemAxon
Polarizability27.55 ųChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-004i-3690000000-20d2133e95fbc6b1f4142017-09-01View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0006-0190000000-fc527e672048d9bf866c2016-08-02View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-004i-0490000000-09182e67659519af87e72016-08-02View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0l1i-0910000000-81f4aa818323e96b54642016-08-02View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0006-0090000000-bd79ad698f8bd9fbb84b2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0006-2490000000-4632cbf11a6dc353d2cf2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0006-9200000000-948170ac23122892a5ad2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0006-0090000000-168fda82142bf345541b2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-002f-0090000000-3dac4efa84856ab164862021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-000i-0910000000-bdfabb283d321aa1d9e32021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0006-0090000000-932ee60351365d51e6112021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0006-1190000000-c3fd5753f8f9a8a098eb2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0006-4910000000-8fac1192455fd2253b722021-10-11View Spectrum
Toxicity Profile
Route of ExposureFrovatriptan is rapidly absorbed from the duodenum, but has low oral bioavailability.
Mechanism of ToxicityThree distinct pharmacological actions have been implicated in the antimigraine effect of the triptans: (1) stimulation of presynaptic 5-HT1D receptors, which serves to inhibit both dural vasodilation and inflammation; (2) direct inhibition of trigeminal nuclei cell excitability via 5-HT1B/1D receptor agonism in the brainstem and (3) vasoconstriction of meningeal, dural, cerebral or pial vessels as a result of vascular 5-HT1B receptor agonism.
MetabolismIn vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan to several metabolites including hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, and several other minor metabolites. Desmethyl frovatriptan has lower affinity for 5-HT1B/1D receptors compared to the parent compound. The N-acetyl desmethyl metabolite has no significant affinity for 5-HT receptors. The activity of the other metabolites is unknown. Route of Elimination: Radiolabeled compounds excreted in urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, together with several other minor metabolites. Less than 10% of frovatriptan was excreted in urine after an oral dose. Half Life: 26 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the acute treatment of migraine attacks with or without aura in adults.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsThere is no direct experience of any patient taking an overdose of Frovatriptan. The maximum single dose of frovatriptan given to male and female patients with migraine was 40 mg (16 times the clinical dose) and the maximum single dose given to healthy male subjects was 100 mg (40 times the clinical dose) without significant adverse events.
TreatmentAs with other 5-HT1 receptor agonists, there is no specific antidote for frovatriptan. The elimination half-life of frovatriptan is 26 hours, therefore if overdose occurs, the patient should be monitored closely for at least 48 hours and be given any necessary symptomatic treatment. (8)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00998
HMDB IDHMDB15133
PubChem Compound ID77992
ChEMBL IDCHEMBL1279
ChemSpider ID70378
KEGG IDNot Available
UniProt IDNot Available
OMIM ID
ChEBI ID350328
BioCyc IDNot Available
CTD IDNot Available
Stitch IDFrovatriptan
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkFrovatriptan
References
Synthesis Reference

Samir Naik, Anthony Crasto, Narendra Joshi, Sachin Srivastava, “Amorphous frovatriptan succinate and process for the preparation thereof.” U.S. Patent US20070299123, issued December 27, 2007.

MSDSNot Available
General References
  1. Markus F, Mikko K: Frovatriptan review. Expert Opin Pharmacother. 2007 Dec;8(17):3029-33. [18001261 ]
  2. Easthope SE, Goa KL: Frovatriptan. CNS Drugs. 2001;15(12):969-76; discussion 977-8. [11735616 ]
  3. Balbisi EA: Frovatriptan: a review of pharmacology, pharmacokinetics and clinical potential in the treatment of menstrual migraine. Ther Clin Risk Manag. 2006 Sep;2(3):303-8. [18360605 ]
  4. Balbisi EA: Frovatriptan succinate, a 5-HT1B/1D receptor agonist for migraine. Int J Clin Pract. 2004 Jul;58(7):695-705. [15311727 ]
  5. Elkind AH, Wade A, Ishkanian G: Pharmacokinetics of frovatriptan in adolescent migraineurs. J Clin Pharmacol. 2004 Oct;44(10):1158-65. [15342617 ]
  6. Jhee SS, Shiovitz T, Crawford AW, Cutler NR: Pharmacokinetics and pharmacodynamics of the triptan antimigraine agents: a comparative review. Clin Pharmacokinet. 2001;40(3):189-205. [11327198 ]
  7. Drugs.com [Link]
  8. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

Target Details
1. 5-hydroxytryptamine receptor 1B
General Function:
Serotonin receptor activity
Specific Function:
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive substances, such as lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. Arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Regulates the release of 5-hydroxytryptamine, dopamine and acetylcholine in the brain, and thereby affects neural activity, nociceptive processing, pain perception, mood and behavior. Besides, plays a role in vasoconstriction of cerebral arteries.
Gene Name:
HTR1B
Uniprot ID:
P28222
Molecular Weight:
43567.535 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. Easthope SE, Goa KL: Frovatriptan. CNS Drugs. 2001;15(12):969-76; discussion 977-8. [11735616 ]
  3. Comer MB: Pharmacology of the selective 5-HT(1B/1D) agonist frovatriptan. Headache. 2002 Apr;42 Suppl 2:S47-53. [12028320 ]
  4. Balbisi EA: Frovatriptan succinate, a 5-HT1B/1D receptor agonist for migraine. Int J Clin Pract. 2004 Jul;58(7):695-705. [15311727 ]
  5. Parsons AA, Raval P, Smith S, Tilford N, King FD, Kaumann AJ, Hunter J: Effects of the novel high-affinity 5-HT(1B/1D)-receptor ligand frovatriptan in human isolated basilar and coronary arteries. J Cardiovasc Pharmacol. 1998 Aug;32(2):220-4. [9700983 ]
  6. Dodick DW, Sandrini G, Williams P: Use of the sustained pain-free plus no adverse events endpoint in clinical trials of triptans in acute migraine. CNS Drugs. 2007;21(1):73-82. [17190530 ]
Target Details
2. 5-hydroxytryptamine receptor 1D
General Function:
Serotonin receptor activity
Specific Function:
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. Regulates the release of 5-hydroxytryptamine in the brain, and thereby affects neural activity. May also play a role in regulating the release of other neurotransmitters. May play a role in vasoconstriction.
Gene Name:
HTR1D
Uniprot ID:
P28221
Molecular Weight:
41906.38 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. Easthope SE, Goa KL: Frovatriptan. CNS Drugs. 2001;15(12):969-76; discussion 977-8. [11735616 ]
  3. Comer MB: Pharmacology of the selective 5-HT(1B/1D) agonist frovatriptan. Headache. 2002 Apr;42 Suppl 2:S47-53. [12028320 ]
  4. Tfelt-Hansen P, De Vries P, Saxena PR: Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy. Drugs. 2000 Dec;60(6):1259-87. [11152011 ]
  5. Deleu D, Hanssens Y: Current and emerging second-generation triptans in acute migraine therapy: a comparative review. J Clin Pharmacol. 2000 Jul;40(7):687-700. [10883409 ]
  6. Jahnichen S, Radtke OA, Pertz HH: Involvement of 5-HT1B receptors in triptan-induced contractile responses in guinea-pig isolated iliac artery. Naunyn Schmiedebergs Arch Pharmacol. 2004 Jul;370(1):54-63. Epub 2004 Jun 8. [15185063 ]